JCI table of contents, 2 April 2004

04/01/04

Hypertension Tamer

Major diseases of the heart, brain, and kidney all have one thing in common: high-blood pressure as a major risk factor. Hypertension afflicts nearly 50 million people in USA, and over 1 billion worldwide. Although hypertension weighs in heavily on world health, its underlying cause for the vast majority of cases is unknown. One of the known components involved in regulating blood pressure is the beta1subunit of the large Ca2+ activated K+ (BK) channel. The beta1 subunit acts to increase the Ca2+- and voltage-sensitivity of the BK channel, and, intriguingly, it is primarily expressed in smooth muscle tissue in vascular walls. Now, Miguel Valverde and colleagues of the Universitat Pompeu Fabra, have found that a specific mutation in the human beta1-subunit gene, KCNMB1, is associated with lower blood pressure. Carrying out a large epidemiological population-based study, the researchers found an very low frequency (3.2%) of the presence of a single nucleotide substitution (G352A), resulting in a glutamic acid-to-lysine change at amino acid position 65, in KCNMB1 in individuals with extremely high diastolic blood pressure as compared to normotensive individuals (21.6%). That this mutation was so rarely found in individuals with such high diastolic pressure suggested that the beta1subunit with this alteration may provide a protective effect against diastolic hypertension. To see if this mutation affects the action of the BK channel, the authors tested mutant beta1 subunit (beta1E65K) in cell culture and showed that beta1E65K alone or in combination with wild-type beta1 subunit further increased the normal Ca2+- and voltage-sensitivity. These data provide biochemical evidence that this mutation alters the activity of the beta1 subunit in a way that affects BK channel activity and thereby impacts on blood pressure. These data provide compelling reason for investigating the therapeutic potential of agents that target the beta1 subunit.

An accompanying commentary by Mark Nelson of the University of Vermont provides detail on our current understanding of the molecular underpinnings of hypertension, and places Valverde and colleagues' work in this context.

TITLE: Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension

AUTHOR CONTACT:
Miguel A. Valverde
Universitat Pompeu Fabra, Barcelona, Spain.
Phone: 34-93-542-2832
Fax: 34-93-542-2802
E-mail: miguel.valverde@edu.upf

View the PDF of this article at: https://www.the-jci.org/press/20347.pdf

ACCOMPANYING COMMENTARY: The beta1 subunit of the Ca2+-sensitive K+ channel protects against hypertension

AUTHOR CONTACT:
Mark T. Nelson
University of Vermont, Burlington, Vermont, USA.
Phone: 802-656-2500
Fax: 802-656-4523
E-mail: Mark.Nelson@uvm.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21388.pdf


Bim Notes in the Neuronal Executioner's Song

Brain damage often results after prolonged seizures as well as after brief or repetitive epileptic seizures. Previous work has indicated that loss of neurons in the hippocampus after seizures may be due to onset of programmed cell death. Members of the Bcl-2 family are known to activate a pathway ending in the release of several caspases, including the 'executioner,' caspase-3. David Henshall and colleagues, of Robert S. Dow Neurobiology Laboratories, investigate molecular members of the programmed cell death pathway and show that reduction of Bim (Bcl-2-interacting mediator of cell death) may provide protection from neuronal loss. The researchers examined Bim expression in both experimentally induced seizures in rats and in patients with temporal lobe epilepsy. In instances of experimentally-produced prolonged seizures that damaged the hippocampus in rats, Bim expression increased. Blocking upstream activators of Bim or using Bim antisense to block Bim expression reduced neuronal damage. Of interest, in the hippocampus of epileptic patients, Bim appeared to be selectively down-regulated. These results suggest a means by which the brain may protect itself from additional neural damage following epileptic seizures. Targeting this molecular pathway may be worthwhile for ameliorating seizure-induced brain injuries.

An accompanying commentary by Jerome Niquet and Claude Wasterlain, of Epilepsy Research Laboratory, place this work in context with the complexity of cell-death pathways and highlight specific areas of future analysis that are still required to understand the molecular mechanisms at play in neuronal damage.

TITLE: Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

AUTHOR CONTACT:
David C. Henshall
Robert S. Dow Neurobiology Laboratories, Portland, Oregan, USA.
Phone: 503-413-5260
Fax: 503-413-5465
E-mail: dhenshall@downeurobiology.org

View the PDF of this article at: https://www.the-jci.org/press/19971.pdf

ACCOMPANYING COMMENTARY: Bim, Bad, and Bax: a deadly combination in epileptic seizures

AUTHOR CONTACT:
Jerome Niquet
Epilepsy Research Laboratory, West Los Angeles, California, USA.
Phone: 310-478-3711 ext. 41974
Fax: 310-268-4856
E-mail: jniquet@ucla.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21478.pdf


Roadblocks in Urine Town

Approximately 1% of newborns present with enlargement of the kidney that results from urine collection in the renal pelvis or calcyses. This can lead to obstructive nephropathy, the most common form of renal failure in infants and children. Obstructive nephropathy is often caused by structural blockage, due to the presence of stones. In many cases, however, the underlying cause seems to be a functional blockage, for which the molecular basis remains unknown. Feng Chen and colleagues, from Washington University School of Medicine, have developed a mouse model of this urinary tract disease by selectively deleting the Cnb1 gene from the mesenchyme of the developing urinary tract. Cnb1 is the regulatory subunit of calcineurin, a Ca2+-dependent serine/threonine phosphatase, which is thought to play a role in kidney function. The researchers found that selective deletion of Cnb1 resulted in a reduction in smooth muscle cell- and other mesenchymal cell-proliferation in the urinary tract, resulting in abnormal development of the renal pelvis and ureter. These defects inhibited normal pyeloureteral peristalsis -- a functional obstruction that ultimately leads to fatal renal failure. This study provides evidence for a direct role for the calcineurin-signaling pathway in urinary tract development and also shows the importance of functional rather than structural defects in the development of obstructive nephropathy.

A commentary by Cathy Medelsohn discusses the work by Chen and colleagues as it relates to our current understanding of kidney and urinary tract development and function.

TITLE: Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

AUTHOR CONTACT:
Feng Chen
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-362-3162
Fax: 314-362-8237
E-mail: fchen@im.wustl.edu

View the PDF of this article at: https://www.the-jci.org/press/20049.pdf

ACCOMPANYING COMMENTARY: Functional obstruction: the renal pelvis rules

AUTHOR CONTACT:
Cathy Mendelsohn
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-1591
Fax: 212-305-6851
E-mail: clm20@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21402.pdf


The APCs of Autoimmune Disease

Automimmune diseases are a complex set of disorders that all result from a failure of the immune system to recognize "self" due to the presence of autoreactive T cells. The body has several means of removing autoreactive T cells, including T cell deletion in the thymus and peripheral tolerance for T cells that escape thymic deletion. These mechanisms, however, fail in some individuals, resulting in an autoimmune response that can be crippling. Many of the factors, both environmental and genetic, involved in autoimmune disease development remain a mystery. Vijay Kuchroo and colleagues of Brigham and Woman's Hospital and Harvard Medical School used autoreactive transgenic T cells in an experimental autoimmune encephalomyelitis (EAE)–resistant mouse strain and now present data showing that the activation state of APCs plays a role in the development of autoimmune diseases (pages 990–997). T cell number and response were the same in both the transgenic EAE-resistant and EAE-sensitive backgrounds; however, the APCs in the EAE-resistant background had a lower activation state and lower T cell stimulating response than those in the EAE-sensitive strain. Furthermore, innate immune receptor activation of the APCs resulted in EAE development even in the resistant background, providing insight into why viral infection is often associated with the onset of certain autoimmune disorders.

TITLE: Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease

AUTHOR CONTACT:
Vijay K. Kuchroo
Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
Phone: 617-525-5350
Fax: 617-525-5333
E-mail: vkuchroo@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/19388.pdf


Monitoring Macrophages Detects Dementia

HIV-associated dementia complex, termed HIV encephalitis, occurs in about one-quarter of infected individuals. Unfortunately, the symptoms and signs of dementia are not usually evident until the late stages of encephalitis, after irreversible damage has occurred. Thus, diagnostic tools for the detection of HIV encephalitis prior to the manifestation of neurological signs would greatly aid in developing therapeutic intervention. Clayton A. Wiley and colleagues, from Presbyterian University Hospital, have tested the use of PET scans to detect and monitor HIV encephalitis progression (pages 981–989). Using a macaque model, they administered radiolabeled ligands for the peripheral benzodiazepine receptor (PBR), which is abundantly expressed on brain macrophages, and used PET imaging to monitor macrophage infiltration in simian immunodeficiency virus–infected (SIV-infected) macaques. They detected increased ligand binding only in the brains of SIV-infected macaques that developed encephalitis. Moreover, histopathological studies enabled them to correlate various stages of SIV encephalitis with levels of radiolabel uptake and binding, indicating that PET scans can be used to observe progression of the disease in addition to facilitating early detection. The development of such diagnostic tools will be of great importance in the care and treatment of HIV-infected patients.

TITLE: PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

AUTHOR CONTACT:
Clayton A. Wiley
Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA.
Phone: 412-647-0765
Fax: 412-647-5602
E-mail: wiley@np.awing.upmc.edu

View the PDF of this article at: https://www.the-jci.org/press/20227.pdf


VEGF-A Versatility

Lymphangiogenesis and hemangiogenesis are both important processes in angiogenesis, which plays a central role in tumor progression, chronic inflammatory disorders, and most blinding ocular diseases. The VEGF family of growth factors is a key contributor to these processes. Previous studies indicated that VEGF-A is primarily responsible for hemangiogenesis, whereas VEGF-C and -D induce lymphangiogenesis. Whether VEGF-A also plays a role in lymphangiogenesis, however, remains unclear. Wayne Streilein and colleagues, from The Schepens Eye Research Institute, addressed this concern by testing the effects of VEGF-A inhibition on both hemangiogenesis and lymphangiogenesis using a mouse model of suture-induced inflammatory corneal neovascularization (pages 1040–1050). By administration of a fusion protein that traps VEGF-A and specifically prevents activation of one of its receptors, VEGFR2, they showed that loss of VEGF-A function fully blocked both hemangiogenesis and lymphangiogenesis after suture placement. Furthermore, VEGF-A inhibition resulted in impaired recruitment of inflammatory cells into the cornea, and selective macrophage depletion in sutured corneas disabled corneal angiogenesis. These findings demonstrate critical roles for VEGF-A and for macrophages in the pathological induction of both hemangiogenesis and lymphangiogenesis and identify important targets for antiangiogenic therapies.

TITLE: VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment

AUTHOR CONTACT:
Claus Cursiefen
The Schepens Eye Research Institute, Boston, Massachusetts, USA.
Phone: 617-912-0100
Fax: 617-912-0101
E-mail: cursiefen@vision.eri.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/20465.pdf


Overcoming Obstacles in Antiangiogenesis Gene Therapy

Antiangiogenic gene therapy strategies against cancer are considered preferable to direct tumor-targeting strategies because tumor cells, with their high somatic mutation frequency, often develop resistance to apoptotic stimuli. Gene therapy in the vasculature, however, also has limitations, including lack of expression specificity and loss of transgene expression due to the body's immune response. Dror Harats and colleagues, from the Sheba Medical Center, have overcome these two obstacles by using a modified promoter for an endothelial cell (EC) protein to drive expression of the hybrid apoptotic induction gene Fas-c (pages 1017–1024). The promoter confers the necessary specificity and also includes modifications to enhance expression in hypoxic and cytokine-rich microenvironments, such as those found in tumor angiogenic vessels. The transgene produces a receptor that, upon activation by TNF-_, initiates the Fas-induced apoptotic pathway. Treatment of two tumor mouse models resulted in tumor growth rate reduction and decreased tumor size. Histology revealed that EC apoptosis was largely responsible for the antitumor effects. Liver analysis further indicated the apoptotic effects were specific to ECs, and the EC-expression restriction of apoptosis enhanced transgene stability by dodging the humoral response. This approach to gene therapy offers the promise of improved anti-angiogenic gene-therapy cancer treatments.

TITLE: Transcription-controlled gene therapy against tumor angiogenesis

AUTHOR CONTACT:
Dror Harats
Sheba Medical Center, Tel Hashomer, Israel
Phone: 972-3-530-2940
Fax: 972-3-534-3521
E-mail: dharats@post.tau.ac.il

View the PDF of this article at: https://www.the-jci.org/press/20007.pdf


Possibilities from the Impossible in Leukemia Patients

The chance finding of a common rearrangement in the variable region of an immunoglobin (Ig) receptor in different individuals is staggeringly unlikely: Ig genes can potentially create over 3.4 million functional rearrangements. Improbable is apparently not impossible, as Nicholas Chiorazzi and colleagues, of the North Shore-LIJ Research Institute, have recently identified remarkably similar B-cell antigen receptors among a group of individuals suffering from B cell chronic lymphocytic leukemia (B-CLL). While B-CLL is the most common of the leukemias found in the Western hemisphere, little is known about what causes the normal B cell in these individuals to undergo leukemic transformation. The unexpected finding of similar Ig rearrangement in the B-cell antigen receptors from this group of patients suggests that some form of selection played a role here, and may therefore provide the first insight into the underlying molecular mechanisms at play in this deadly disease.

An accompanying commentary by J. Donald Capra and Grant Kolar of the Oklahoma Medical Research Foundation, detail what is understood about B-CLL and discuss this unusual finding as it relates to this disease and other immunological disorders.

TITLE: Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia

AUTHOR CONTACT:
Nicholas Chiorazzi
North Shore-LIJ Research Institute, Manhasset, New York, USA.
Phone: 516-562-1085
Fax: 516-562-1022
E-mail: nchizzi@nshs.edu

View the PDF of this article at: https://www.the-jci.org/press/19399.pdf

ACCOMPANYING COMMENTARY: Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

AUTHOR CONTACT:
J. Donald Capra
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Phone: 405-271-7210
Fax: 405-271-8237
E-mail: donald-capra@omrf.ouhsc.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21412.pdf


Factoring in New Treatment Strategies for Hemophilia

Hemophilia is an X-chromosome linked bleeding disorder caused by mutations in the genes encoding blood coagulation factors Factor VIII (FVIII) and FIX. The standard treatment is replacement of the missing proteins intravenously. Complications often arise, however, when patients develop antibodies to these clotting factors, neutralizing treatment. An alternative treatment is the infusion of a recombinant Factor VII (FVII), a procoagulant reaction activator that is independent of FVIII and FIX. But this treatment is extremely costly and the recombinant FVII has a very short half-life, translating into more treatments. Katherine High and colleagues, of the Abramson Research Center in Philadelphia, provide a new strategy to get around current FVII treatment problems. Using a novel recombinant adeno-associated virus vector they deliver a modified FVII transgene that is intracellularly processed and secreted in its activated form. Using a hemophilia mouse model, they show long-term FVII expression and were able to correct the bleeding phenotype. These results indicate a strong potential for this strategy to be useful for treating human hemophilia and possibly other bleeding disorders.

TITLE: Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

AUTHOR CONTACT:
Katherine A. High
Abramson Research Center, Philadelphia, Pennsylvania, USA.
Phone: 215-590-4521
Fax: 215-590-3660
E-mail: high@email.chop.edu

View the PDF of this article at: https://www.the-jci.org/press/20106.pdf


Skinning an Immune Response

To be most protective, vaccines need to induce a strong systemic and mucosal immune response. Transcutaneous immunization (TCI), or application of an antigen to the surface of the skin to induce an immune response, is a particularly desirable form of vaccination given its ability to block pathogens at their point of entry. The details of the mechanisms through which TCI triggers such a response and its relative safety and efficacy remain unknown. Igor Belyakov and colleagues, of the National Cancer Institute, investigate the process by which TCI generates a protective immunity using an HIV peptide as an antigen in a mouse model system. The researchers showed TCI with the HIV peptide in mice resulted in activation of dendritic cells. The dendritic cells then migrated from the skin to the gut mucosa where they presented antigen to the resident lymphocytes. The results from this study add significant information to our understanding of TCI action, and indicate that it is a safe and effective strategy for developing pathogen protection.

TITLE: Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells

AUTHOR CONTACT:
Igor Belyakov
National Cancer Institute NIH, Bethesda, Maryland, USA.
Phone: 301-435-8341
Fax: 301-402-0549
E-mail: belyakov@mail.nih.gov

View the PDF of this article at: https://www.the-jci.org/press/20261.pdf


T Cell Balancing Act in Hepatitus C Chronic Infection

One of the main puzzles of hepatitis C viral (HCV) infection relates to how HCV can establish a persistent infection in the presence of a large number of T cells that are specific to HCV antigens, and should therefore result in HCV clearance from the organism's system. Upon HCV infection, HCV-specific CD8+ T-cells are massively recruited to the liver, but these cells have been shown to be inefficient in their activity against HCV infected cells. Now, Vincenzo Barbaba and colleagues of Universita degli Studi di Roma present the first data concerning the underlying reason for the inefficient activity of these T cells. Analyzing chronic HCV patients, the researchers found that the number of CD8+ regulatory T-cells (CD8+ Treg) was likewise increased. These CD8+ Treg cells produced large amounts of interleukin-10 (IL-10). Application of inhibitors to IL-10 restored CD8+ T-cell activity. This work marks the pivotal role that these regulatory T-cells play in controlling hepatic CD8+ T cell action during HCV infection and that the concomitant appearance off these two cell types may be the main factor in the establishment of chronic infection.

TITLE: Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection

AUTHOR CONTACT:
Vincenzo Barnaba
Universita degli Studi di Roma, Rome, Italy.
Phone: 39-06-445-3994
Fax: 39-06-4938-3333
E-mail: vincenzo.barnaba@uniroma1.it

View the PDF of this article at: https://www.the-jci.org/press/20515.pdf


New Paths for Platelet Fragmentation in Thrombocytopenia

One of the complications of HIV infection is the development of immunologic thrombocytopenia. Peripheral destruction of platelets through antibody-induced platelet fragmentation is increased in this disease. Previous reports have indicated Ab-induced fragmentation was due to the generation of reactive oxygen species (ROS), including peroxide. An active NADPH oxidase pathway is required for ROS generation. Simon Karpatkin and colleagues of New York University School of Medicine now show that Ab-induced fragmentation also requires activation by the platelet 12-lypoxygenase (12-LO) pathway. The discovery of a role for the 12-LO pathway in thrombocytopenia provides a new area to explore for reversing or preventing this disease.

TITLE: Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway

AUTHOR CONTACT:
Simon Karpatkin
New York University School of Medicine, New York, New York, USA.
Phone: 212-263-5609
Fax: 212-263-0695
E-mail: simon.karpatkin@med.nyu.edu

View the PDF of this article at: https://www.the-jci.org/press/20726.pdf

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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Rudyard Kipling